Approximately 10-20% of hemophiliacs who receive multiple factor VIII treatments develop alloantibodies that inactivate factor VIII. The development of such factor VIII inhibitors is a serious complication which can result in major bleeding episodes that are difficult to treat. Current therapies include high dose human or porcine factor VIII, steroids, intravenous immune globulin, plasmapheresis, and recombinant factor VIIa. Similar problems may occur in patients undergoing treatment for factor V deficiency. Despite these interventions, many patients require large amounts of blood products during bleeding episodes. Accordingly, there is a continued need for new ways of diagnosing and combating the development of inhibitory alloantibodies in patients undergoing treatment with blood coagulation proteins.
D. Scandella et al., Blood 74, 1618 (1989), describe an E. coli expression system for the epitope mapping of factor VIII inhibitors.
D. Scandella et al., Thromb. Haemost. 67, 665 (1992) describe a baculovirus expression system for epitope mapping of factor VIII with recombinant factor VIII peptides.
U.S. Pat. No. 5,004,803 to R. Kaufman and D. Pittman describe recombinant DNA coding for factor VIII in which its B domain is replaced with the B domain peptide sequence of factor V. This reference is concerned with obviating problems in the secretion of factor VIII, and not with the active forms of the blood coagulation protein. Note that the sequences of human factor V and VIII are about 40% identical except in the B domain, where there is little homology. See, e.g., J. Toole et al. Nature 312, 342 (1984); G. Vehar et al., Nature 312, 337 (1984).